Method of treating mental disorders using D4 and 5-HT2A antagonists, inverse agonists or partial agonists

ABSTRACT

The present invention relates to methods of treating of the underlying dysregulation of the emotional functionality of mental disorders (i.e. affect instability-hypersensitivity-hyperaesthesia-dissociative phenomena- . . . ) using compounds and compositions of compounds having D4 and/or 5-HT2A antagonistic, partial agonistic or inverse agonistic activity for. The invention also relates to methods comprising administering to a patient diagnosed as having a neuropsychiatric disorder a pharmaceutical composition containing (i) compounds having D4 antagonistic, partial agonistic or inverse agonistic activity and/or (ii) compounds having 5-HT2A antagonistic, partial agonistic or inverse agonistic, and/or (iii) any known medicinal compound and compositions of said compounds. The combined D4 and 5-HT2A antagonistic, partial agonistic or inverse agonistic effects may reside within the same chemical or biological compound or in two different chemical and/or biological compounds.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. application Ser. No. ______,filed Dec. 2, 2003, entitled “Method of Treating Mental Disorders UsingD4 and 5-HT2A Antagonists, Inverse Agonists or Partial Agonists,” andnaming Erik Buntinx as the inventor.

FIELD OF THE INVENTION

The invention relates to the field of neuropsychiatry. Morespecifically, the invention relates to methods of treating theunderlying dysregulation of the emotional functionality of mentaldisorders using of compounds having D4 and/or 5-HT2A antagonist, inverseagonist or partial agonist activity.

BACKGROUND OF THE INVENTION

Clinical or real effectiveness of psychopharma is very rare via commonpooping-out, many treatment-refractory patients and up to half ofpatients fail to attain remission (S. M. Stahl, EssentialPsychopharmacology, 2000). Implications of not attaining remission forMental Disorders are increased relapse rates, continuing functionalimpairment and increased suicide rate.

Clinical causes of not attaining remission by the CurrentPsychopharmacological Compounds are inadequate early treatment,underlying dysregulation of the emotional functionality (affectinstability-hypersensitivity-hyperaesthesia-dissociative phenomena . . .) and competitive antagonism.

Dysregulation of the HPA axis has frequently reported in patients withpsychiatric disorders, and is among the most robustly demonstratedneurobiological changes among psychiatric patients (D. A. Gutman and C.B. Nemeroff, Biological Psychiatry, 2002). The resulting elevated plasmacortisol concentrations leads to an enhanced binding of serotonin forthe 5-HT2A receptor (E. A. Young, Arch Gen Psychiatry/Vol 60, January2003).

Results suggest that cortical D2 dopamine receptors are a common targetof traditional and atypical antipsychotics for therapeutic action.Higher in vivo binding to the D2 receptors in the cortex than in thebasal ganglia is suggested as an indicator of favourable profile for aputative antipsychotic compound (X. Xiberas and J. L. Martinot; TheBritish Journal of Psychiatry (2001) 179: 503-508).

Data demonstrate that dopamine D4 receptors play an important role inthe induction of behavioral sensitization to amphetamine andaccompanying adaptations in pre- and postsynaptic neural systemsassociated with the mesolimbocortical dopamine projections (D. L.Feldpausch et al; The journal of pharmacology and experimentaltherapeutics Vol. 286, Issue 1, 497-508, July 1998). Further, resultsshow that dopamine D4 receptor antagonism in the brain does not resultin the same neurochemical consequences (increased dopamine metabolism orhyperprolactinemia) observed with typical neuroleptics (Smita Patel etal; The journal of pharmacology and experimental therapeutics Vol. 283,Issue 2, 636-647,1997).

However, the selective D4 dopamine receptor antagonist L-745,870 wasineffective as an antipsychotic for the treatment of neurolepticresponsive inpatients with acute schizophrenia (Kramer M S et al; ArchGen Psychiatry 1997 December;54(12):1080.)

There is thus a growing need for a more efficient therapy and moreefficient, selective and efficacious medicaments for treating mentaldisorders.

SUMMARY OF THE INVENTION

The present invention invention relates to the use of compounds andpharmaceutical compositions having D4 and/or 5-HT2A antagonistic,partial agonistic or inverse agonistic activity for the treatment of theunderlying dysregulation of the emotional functionality of mentaldisorders (i.e. affectinstability-hypersensitivity-hyperaesthesia-dissociative phenomena- . .. ) and to methods entailing administering to a patient diagnosed ashaving a neuropsychiatric disorder a pharmaceutical compositioncontaining (i) compounds having D4 antagonistic, partial agonistic orinverse agonistic activity and/or (ii) compounds having 5-HT2Aantagonistic, partial agonistic or inverse agonistic, and/or (iii) anyknown medicinal compound and compositions of compounds. The combined D4and 5-HT2A antagonistic, partial agonistic or inverse agonistic effectsmay reside within the same chemical or biological compound or in twodifferent chemical or two different biological compounds or in acombination of a chemical & biological compound.

In a more preferred embodiment of the invention, said composition isadministered to a patient in a dose ranging between 0.5 μg and 300 mgfor each of the active ingredients.

According to a first embodiment the invention relates to a method fortreating a disease or disorder with an underlying dysregulation of theemotional functionality comprising the use of a compound having (i) aselective affinity for the Dopamine-4 (D4) receptor with a pKi valueequal to or higher than 8 towards the D4 receptor and less than 8towards other Dopamine receptors, and (ii) a selective affinity for the5-HT2A receptor with a pKi value equal to or higher than 8 towards the5-HT2A receptor and less than 8 towards other 5HT receptors and whereinsaid compound is administered to a patient in a dose ranging between 5and 15 mg of the active ingredient, preferably said compound isPIPAMPERONE.

In a preferred embodiment, the disease or disorder to be treated withPIPAMPERONE is selected from the group comprising anxiety disorders,eating disorders, premenstrual syndrome, somatoform disorders,factitious disorders, dissociative disorders, sexual and gender identitydisorders, sleep disorders, adjustment disorders, cognitive disorders,impulse control disorders, pervasive development, attention-deficit anddisruptive behaviour disorders, substance-related disorders, personalitydisorders, psychological factors affecting medical conditions,malingering, antisocial behaviour, bereavement, occupational, identity,phase of life, academic problem, problems related to abuse or neglect.

The invention also relates to a method of treating a disease or disorderwith an underlying dysregulation of the emotional functionality whereina second compound is administered simultaneously with, separate from orsequential to the first compound as defined above to augment thetherapeutic effect of said second compound on said disease, or toprovide a faster onset of the therapeutic effect of said second compoundon said disease. Preferably, the disease or disorder to be treated isselected from the group comprising mood disorders, anxiety disorders,schizophrenia and other psychotic disorders, eating disorders,premenstrual syndrome, somatoform disorders, factitious disorders,dissociative disorders, sexual and gender identity disorders, sleepdisorders, adjustment disorders, cognitive disorders, impulse controldisorders, pervasive development, attention-deficit and disruptivebehaviour disorders, substance-related disorders, personality disorders,psychological factors affecting medical conditions, malingering,antisocial behaviour, bereavement, occupational, identity, phase oflife, academic problem, problems related to abuse or neglect.

In a preferred embodiment, the invention relates to any of the methodsdescribed herein wherein the first compound is administered daily atleast one day before administering said second compound. Preferably saidsecond compound is a selective serotonine re-uptake inhibitor, forinstance chosen from the group comprising, but not limited to,CITALOPRAM, fluoxetine, venlafaxine, fluvoxamine, paroxetine,sertraline, milnacipran and duloxetine or a pro-drug or an activemetabolite thereof, or a pharmaceutically acceptable salt thereof. Morepreferably, said serotonin re-uptake inhibitor is CITALOPRAM and isadministered in a dose ranging between 10 and 40 mg of the activeingredient.

According to another preferred embodiment, said second compound is anorepinephrine re-uptake inhibitor, preferably chosen from the groupcomprising, but not limited to, tandamine, pirandamine, ciclazindol,fluparoxan, lortalamine, talsupram, talopram, prindamine, nomifensine,viloxazine, tomoxetine, duloxetine, venlafaxine, milnacipran andreboxetine, or a pro-drug or an active metabolite thereof, or apharmaceutically acceptable salt thereof.

According to another preferred embodiment, said second compound is aneuroleptic agent, preferably chosen from the group comprising, but notlimited to, chlorpromazine, haloperidol, perphenazine, thioridazine,mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine,risperidone, ziprasidone, quetiapine, sertindole, aripiprazole,sonepiprazole, blonanserin, iloperidone, perospirone, raclopride,zotepine, DU-127090, ORG-5222, SM-13496, amisulpride, CP-361428, Lu35-138, balaperidone, S-18327, WAY-135452, eplivanserin, E-5842,SR-31742, NE-100, osanetant, SR-141716, SR-48692, BSF-201640,BSF-190555, LAX-101a, sarizotan, CX-691 and SB-271046, or a pro-drug oractive metabolite thereof, or a pharmaceutically acceptable saltthereof.

According to another preferred embodiment, said second compound is aneurokinin-1 (NK1) antagonist, preferably chosen from the groupcomprising but not limited to MK-0869, GW597599, GW679769, GW823296,Compound A, NKP608, CP-96345(cis-3-(2-methoxybenzyl-amino-2-benzhydrylquinuclidine), CP-122721,CP-99994, GR-82334(D-Pro9-[Spiro-y-lactam]-Leu10,Trp11)-Physalaemin(1-11)), R673, TAK-637,RPR100893 (perhydroisoindolol), RP-67580, LY303870, SR-140333 andtrans-4-hydroxy-1-(1H-indol-3-ylcarbonyl)-L-prolyl-N-methyl-N-(phenylmethyl)-L-tyrosineamide(a derivative of FK888), or a pro-drug or an active metabolite thereof,or a pharmaceutically acceptable salt thereof.

More preferably, said second compound is MK-0869 and is administered ina dose ranging between 10 and 160 mg of the active ingredient, even morepreferred is a dose of 80 mg of the active ingredient.

The invention also relates to a method for treating a disease ordisorder with an underlying dysregulation of the emotionalfunctionality, for instance a method for treating a disease or disorderwith an underlying dysregulation of the emotional functionality, forinstance, selected from the group comprising mood disorders, anxietydisorders, schizophrenia and other psychotic disorders, eatingdisorders, premenstrual syndrome, somatoform disorders, factitiousdisorders, dissociative disorders, sexual and gender identity disorders,sleep disorders, adjustment disorders, cognitive disorders, impulsecontrol disorders, pervasive development, attention-deficit anddisruptive behaviour disorders, substance-related disorders, personalitydisorders, psychological factors affecting medical conditions,malingering, antisocial behaviour, bereavement, occupational, identity,phase of life, academic problem, problems related to abuse or neglect;comprising the use of a composition comprising a first compound having(i) a selective affinity for the D4 receptor with a pKi value equal toor higher than 8 towards the D4 receptor and less than 8 towards otherDopamine receptors, and a second compound having (ii) a selectiveaffinity for the 5-HT2A receptor with a pKi value equal to or higherthan 8 towards the 5-HT2A receptor and less than 8 towards other 5HTreceptors.

In a preferred embodiment of the invention, said first compound ischosen from the group comprising PIPAMPERONE, FANANSERIN, L-745,870,PNU-101387G and U-101387 and wherein said second compound is chosen fromthe group comprising PIPAMPERONE, FANANSERIN, ORG 5222, ZOTEPINE,OLANZEPINE, CLOZAPINE, S16924, S18327, AMPEROZIDE, SERTINDOLE, MDL100.907, TIOSPIRONE, FLUSPIRILENE, OCAPERIDONE, RISPERIDONE andZIPRASIDONE or a pro-drug or an active metabolite thereof, or apharmaceutically acceptable salt thereof.

In a more preferred embodiment said composition is administered to apatient in a dose ranging between 0.5 μg and 300 mg for each of theactive ingredients.

According to separate embodiments of the invention, for the followingcompounds, the following doses (daily doses) are preferred: PIPAMPERONE:5 to 15 mg; ORG 5222: 1-10 mg; OLANZEPINE: 1-10 mg; CLOZAPINE: 1-200 mg;SERTINDOLE: 0.5-4 mg; OCAPERIDONE: 0.5-2 MICROGRAM; RISPERIDONE: 0.5-2MG and ZIPRASIDONE: 1-20 MG.

According to yet another embodiment, the invention relates to acomposition as defined above fro treating a disease or disorder with anunderlying dysregulation of the emotional functionality, for instance,selected from the group comprising mood disorders, anxiety disorders,schizophrenia and other psychotic disorders, eating disorders,premenstrual syndrome, somatoform disorders, factitious disorders,dissociative disorders, sexual and gender identity disorders, sleepdisorders, adjustment disorders, cognitive disorders, impulse controldisorders, pervasive development, attention-deficit and disruptivebehaviour disorders, substance-related disorders, personality disorders,psychological factors affecting medical conditions, malingering,antisocial behaviour, bereavement, occupational, identity, phase oflife, academic problem, problems related to abuse or neglect; whereinsaid composition is administered simultaneously with, separate from orsequential to a third compound to augment the therapeutic effect of saidthird compound on said disease or to provide a faster onset of thetherapeutic effect of said third compound on said disease.

According to a preferred embodiment, said third compound is a selectiveserotonin re-uptake inhibitor. In a preferred embodiment, the first andsecond compound are administered daily at least one day beforeadministering said third compound. Preferably said third compound is aselective serotonin re-uptake inhibitor chosen from the group comprisingCITALOPRAM, fluoxetine, venlafaxine, fluvoxamine, paroxetine,sertraline, milnacipran and duloxetine or a pro-drug or an activemetabolite thereof, or a pharmaceutically acceptable salt thereof. Morepreferably said serotonin re-uptake inhibitor is CITALOPRAM and isadministered in a dose ranging between 10 and 40 mg of the activeingredient.

According to another preferred embodiment, said third compound is anorepinephrine re-uptake inhibitor, preferably chosen from the groupcomprising, but not limited to, tandamine, pirandamine, ciclazindol,fluparoxan, lortalamine, talsupram, talopram, prindamine, nomifensine,viloxazine, tomoxetine, duloxetine, venlafaxine, milnacipran andreboxetine, or a pro-drug or an active metabolite thereof, or apharmaceutically acceptable salt thereof.

According to another preferred embodiment, said third compound is aneuroleptic agent, preferably chosen from the group comprising, but notlimited to, chlorpromazine, haloperidol, perphenazine, thioridazine,mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine,risperidone, ziprasidone, quetiapine, sertindole, aripiprazole,sonepiprazole, blonanserin, iloperidone, perospirone, raclopride,zotepine, DU-127090, ORG-5222, SM-13496, amisulpride, CP-361428, Lu35-138, balaperidone, S-18327, WAY-135452, eplivanserin, E-5842,SR-31742, NE-100, osanetant, SR-141716, SR-48692, BSF-201640,BSF-190555, LAX-101a, sarizotan, CX-691 and SB-271046, or a pro-drug oractive metabolite thereof, or a pharmaceutically acceptable saltthereof.

According to another preferred embodiment, said third compound is an NK1antagonist, preferably chosen from the group comprising but not limitedto MK-0869, GW597599, GW679769, GW823296, Compound A, NKP608, CP-96,345(cis-3-(2-methoxybenzyl-amino-2-benzhydrylquinuclidine), CP-122721,CP-99994, GR-82334(D-Pro9-[Spiro-y-lactam]-Leu10,Trp11)-Physalaemin(1-11)), R673, TAK-637,RPR100893 (perhydroisoindolol), RP-67580, LY303870, SR-140333 andtrans-4-hydroxy-1-(1H-indol-3-ylcarbonyl)-L-prolyl-N-methyl-N-(phenylmethyl)-L-tyrosineamide(a derivative of FK888), or a pro-drug or an active metabolite thereof,or a pharmaceutically acceptable salt thereof.

More preferably, said third compound is MK-0869 and is administered in adose ranging between 10 and 160 mg of the active ingredient; even morepreferred in a dose of 80 mg of the active ingredient.

In a further embodiment, the invention also relates to a method fortreating a muscoskeletal disease or disorder comprising the use of acompound having (i) a selective affinity for the Dopamine-4 (D4)receptor with a pKi value equal to or higher than 8 towards the D4receptor and less than 8 towards other Dopamine receptors, and (ii) aselective affinity for the 5-HT2A receptor with a pKi value equal to orhigher than 8 towards the 5-HT2A receptor and less than 8 towards other5HT receptors, or a composition comprising a first compound having aselective affinity for the D4 receptor with a pKi value equal to orhigher than 8 towards the D4 receptor and less than 8 towards otherDopamine receptors, and a second compound having a selective affinityfor the 5-HT2A receptor with a pKi value equal to or higher than 8towards the 5-HT2A receptor and less than 8 towards other 5HT receptor,characterized in that said compound or composition is administeredsimultaneously with, separate from or sequential to a COX-2 inhibitor toaugment the therapeutic effect of said COX-2 inhibitor or to provide afaster onset of the therapeutic effect of said COX-2 inhibitor.

According to a preferred embodiment, the musculoskeletal disease ordisorder is selected from the group comprising, but not limited to,rheumatoid arthritis, osteoarthritis or ankylosing spondylitis.

In a further preferred embodiment, the COX-2 inhibitor is chosen fromthe group comprising, but not limited to, celecoxib, rofecoxib,meloxicam, piroxicam, deracoxib, parecoxib, valdecoxib, etoricoxib, achromene derivative, a chroman derivative,N-(2-cyclohexyloxynitrophenyl)-methane sulfonamide, COX189, ABT963 andJTE-522, or a pro-drug or active metabolite thereof, or apharmaceutically acceptable salt thereof.

The invention also relates to a method for preparing a compound having aselective D4 and 5-HT2A antagonist, reverse agonist or partial agonistactivity comprising the following steps: (a) measuring the selectiveaffinity of a test compound to the D4 receptor and selecting a compoundthat has a pKi value equal to or greater than 8 towards the D4 receptorin respect to all the other D receptors, and measuring the selectiveefficacy of the selected compound to the D4 receptor and selecting acompound which is a selective antagonist, inverse agonist or partialagonist of the D4 receptor; (b) measuring the selective affinity of atest compound to the 5-HT2A receptor and selecting a compound that has apKi value equal to or greater than 8 towards the 5-HT2A receptor inrespect to all the other 5HT receptors, and measuring the selectiveefficacy of the selected compound to the 5-HT2A receptor and selecting acompound which is a selective antagonist, inverse agonist or partialagonist of the 5-HT2A receptor; (c) identifying a compound which isselected in (a) and (b), (d) preparing the compound identified in (c).

The invention further also relates to a compound prepared by thedescribed method.

DETAILED DESCRIPTION OF THE INVENTION

The present inventor has surprisingly found that compounds which have ahigh selective affinity towards the 5-HT2A receptor and which, at thesame time have a high selective affinity towards the Dopamine-4 (D4)receptor show an improved effect in treating underlying dysregulation ofthe emotional functionality of mental disorders.

The compounds according to the invention may be chemical or biologicalin nature, or may be chemically synthesised. Preferably, the compoundsof the invention are provided as a pharmaceutically acceptable salt.

One example of such a compound which has both a selective affinity forthe 5-HT2A receptor with a pKi value equal to or higher than 8 towardsthe 5-HT2A receptor and less than 8 towards other 5HT receptors, and aselective affinity for the D4 receptor with a pKi value equal to orhigher than 8 towards the D4 receptor and less than 8 towards otherDopamine receptors is PIPAMPERONE. PIPAMPERONE is the conventional namegiven for the compound of the formula1′-[3-(p-Fluorobenzoyl)propyl]-[1,4′-bipiperidine]-4′-carboxamide.PIPAMPERONE is also the active ingredient of Dipiperon (Janssen, CilagB. V).

Further, the present inventor has surprisingly found that the dosage ofactive ingredient for PIPAMPERONE in treatment could be very lowcompared to conventionally used dosages. Preferred dosages which,according to the invention, have been shown to be effective for treatingthese mental disorders, range between 5 and 15 mg per day or between 5and 10 mg per day. More preferably, dosages of 5, 6, 7, 8, 9, 10, 11,12, 13, 14 or 15 mg per day are used in treatment of the diseases of theinvention. In conventional PIPAMPERONE treatment, the active ingredientis available in tablets of 40 mg per tablet or in solutions of 2 mg perdrop. Conventional usage of high doses ranging from 40 to 360 mg isprescribed. For instance for children up to the age of 14, a dosescorresponding with 2 to 6 mg per kg body weight is conventionallyprescribed. The high selective affinity of PIPAMPERONE towards the5-HT2A receptor and the D4 receptor is reflected in the low dosage whichis needed for the treatment of the mental diseases listed below and alsocontributes to the efficacy of the treatment.

The mental disorders which can be treated using PIPAMPERONE in a monotherapy at such low doses are for instance anxiety disorders, eatingdisorders, premenstrual syndrome, somatoform disorders, factitiousdisorders, dissociative disorders, sexual and gender identity disorders,sleep disorders, adjustment disorders, cognitive disorders, impulsecontrol disorders, pervasive development, attention-deficit anddisruptive behaviour disorders, substance-related disorders, personalitydisorders, psychological factors affecting medical conditions,malingering, antisocial behaviour, bereavement, occupational, identity,phase of life, academic problem, problems related to abuse or neglect.

Mental disorders such as depression are commonly treated with serotoninre-uptake inhibitors. Unfortunately, however, these compounds can giverise to side effects in use. Moreover, a substantial problem in mosttreatment of mental disorders is the non-response to selective serotoninre-uptake inhibitors (SSRIs). Also the onset of the therapeutic effectcan be delayed undesirable.

A problem to be solved by the present invention is thus the provision ofa more efficient therapy and efficient, highly selective and efficaciousmedicaments for treating mental disorders.

The inventor has found that the non-response to selective serotoninre-uptake inhibitors (SSRIs) in depression may be declared by (partial)inhibition of the 5-HT1A stimulation via 5-HT2A stimulation.Des-inhibition thereof via 5-HT2A antagonism seems to be an answer tothis problem.

The present inventor has found that a simultaneous or foregoingtreatment with a compound having a high selective 5-HT2A antagonist,inverse agonist or partial agonist activity, could lead to a greaterresponse towards SSRIs. However, not all compounds exhibiting 5-HT2Aantagonism are useful: competition between 5-HT2A stimulation viaserotonin and 5-HT2A antagonism via the compound could be responsiblefor the lack of more efficacy of compounds which have both a selectiveserotonin re-uptake inhibitory and 5-HT2A antagonist profile, such astrazodone and nefazodone.

The present inventor has further surprisingly found that a simultaneousor foregoing treatment with a compound having a high selective D4antagonist, inverse agonist or partial agonist activity in combinationwith a compound having a high selective 5-HT2A antagonist, inverseagonist or partial agonist activity could lead to a greater responsetowards SSRIs.

The present inventor has found that a compound which binds to the 5-HT2Areceptor with a pKi of at least 8 but for which the binding affinity, iepKi, towards other 5HT receptors is less than 8 in combination with acompound which has a high selective affinity for the D4 receptor, i.e.which bind to the D4 receptor with a pKi of at least 8 but for which thebinding affinity, ie pKi, towards other dopamine receptors is less than8 also show such an improved effect in treatment. These effects, ie D4antagonism, inverse agonism or partial agonism and 5-HT2A antagonism,inverse agonism or partial agonism, preferably reside in the samecompound. In other embodiments of the invention, these effects reside inseparate compounds.

‘Other 5HT receptors’ as used herein are for instance 5-HT1 receptors(i.e. 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F), 5-HT2B, 5-HT2C, 5-HT6(rat) and 5-HT7 (rat).

5-HT2A responsive compounds according to the invention are, for instancePIPAMPERONE, FANANSERIN, L-745,870, PNU-101387G and U-101387. All thesecompounds are known in the art and are to be used in doses according tothe supplier's or physician's prescription.

By the expression ‘selective affinity for the 5-HT2A receptor’ is meantthat the receptor has a higher affinity for the 5-HT2A receptor than forother 5-HT receptors.

Preferably, the compounds of the invention which have a selectiveaffinity for the 5-HT2A receptor, are compounds which have a pKi valueequal to or higher than 8 towards the 5-HT2A receptor and less than 8towards other 5HT receptors, as can be measured, for instance by methodsknown in the art. For instance, the “NIMH Psychoactive Drug ScreeningProgram (PDSP)” K_(i) database http://kidb.cwru.edu/nimh/5htp.php), is aunique resource in the public domain which provides information on theabilities of drugs to interact with an expanding number of moleculartargets. The PDSP K_(i) database serves as a data warehouse forpublished and internally-derived pKi, or affinity, values for a largenumber of drugs and drug candidates at an expanding number of G-proteincoupled receptors, ion channels, transporters and enzymes. The PDSPinternet site also provides for commonly used protocols and assays formeasuring pKi values of 5HT receptors.

The expression ‘selective affinity for the D4 receptor’ means that thereceptor has a higher affinity for the Dopamine D4 receptor than forother Dopamine receptors.

D4 responsive compounds according to the invention are, for instance,PIPAMPERONE, FANANSERIN, ORG 5222, ZOTEPINE, OLANZEPINE, CLOZAPINE,S16924, S18327, AMPEROZIDE, SERTINDOLE, MDL 100.907, TIOSPIRONE,FLUSPIRILENE, OCAPERIDONE, RISPERIDONE and ZIPRASIDONE. All thesecompounds are known in the art and are to be used in doses according tothe supplier's or physician's prescription.

‘Other Dopamine receptors’ are, for instance, D1, D2 and D3.

pKi values of test compounds for Dopamine receptors can be measuredusing commonly known assays.

Compounds which have a selective affinity for the D4 receptor preferablyhave a pKi value equal to or higher than 8 towards the D4 receptor andless than 8 towards other Dopamine receptors.

A preferred example of a compound which has both a selective affinityfor the 5-HT2A receptor with a pKi value equal to or higher than 8towards the 5-HT2A receptor and less than 8 towards other 5HT receptors,and a selective affinity for the D4 receptor with a pKi value equal toor higher than 8 towards the D4 receptor and less than 8 towards otherDopamine receptors and which is therefore useful in a combinationtherapy is PIPAMPERONE.

Table 1 illustrates the selective affinity of for instance PIPAMPERONEfor the 5-HT2A and for the D4 receptor. In addition, Table 1 alsoillustrates the low or absence of affinity of PIPAMPERONE for otherreceptors such as the adrenergic receptors Alpha 1A, Alpha 2A, Alpha 2B,Alpha 2C, Beta1, Beta2, and the histamine receptor H1. As such, treatingpatients with PIPAMPERONE will provide for less side effects whichotherwise result from simultaneous stimulation of other receptors.Therefore, and according to preferred embodiments, useful compoundsaccording to the invention not only have a selective 5-HT2A and/or D4affinity but also a low affinity for other receptors such as theadrenergic and histamine receptors.

The low dosage which can be used in PIPAMPERONE treatment, as alreadydescribed earlier, contributes to the high selective affinity of thecompound towards the 5-HT2A receptor and the D4 receptor and thereforealso to the efficacy of the treatment.

The mental disorders which can be treated using compounds having a highselective affinity for the 5-HT2A and D4 receptor, for instancePIPAMPERONE, in a combination therapy with an SSRI are for instance mooddisorders, anxiety disorders, schizophrenia and other psychoticdisorders, eating disorders, premenstrual syndrome, somatoformdisorders, factitious disorders, dissociative disorders, sexual andgender identity disorders, sleep disorders, adjustment disorders,cognitive disorders, impulse control disorders, pervasive development,attention-deficit and disruptive behaviour disorders, substance-relateddisorders, personality disorders, psychological factors affectingmedical conditions, malingering, antisocial behaviour, bereavement,occupational, identity, phase of life, academic problem, problemsrelated to abuse or neglect.

These diseases and their diagnosis are very clearly defined in the“Diagnostic and Statistical Manual of Mental Disorders” published by theAmerican Psychiatric Association. This manual sets forth diagnosticcriteria, descriptions and other information to guide the classificationand diagnosis of mental disorders and is commonly used in the field ofneuropsychiatry. It is for instance available on the internet under:http://www.behavenet.com/capsules/disorders/dsm4tr.htm.

According to a preferred embodiment, the invention thus relates to theuse of a compound having a high selective affinity for the 5-HT2A and D4receptor in combination with a selective serotonin re-uptake inhibiter,for instance chosen from the group comprising CITALOPRAM, fluoxetine,venlafaxine, fluvoxamine, paroxetine, sertraline, milnacipran andduloxetine or a pro-drug or an active metabolite thereof, or apharmaceutically acceptable salt thereof.

The terms “treatment”, “treating”, and the like, as used herein includeamelioration or elimination of a developed mental disease or conditiononce it has been established or alleviation of the characteristicsymptoms of such disease or condition. As used herein these terms alsoencompass, depending on the condition of the patient, preventing theonset of a disease or condition or of symptoms associated with a diseaseor condition, including reducing the severity of a disease or conditionor symptoms associated therewith prior to affliction with said diseaseor condition. Such prevention or reduction prior to affliction refers toadministration of the compound or composition of the invention to apatient that is not at the time of administration afflicted with thedisease or condition. “Preventing” also encompasses preventing therecurrence or relapse-prevention of a disease or condition or ofsymptoms associated therewith, for instance after a period ofimprovement. It should be clear that mental conditions may beresponsible for physical complaints. In this respect, the term“treating” also includes prevention of a physical disease or conditionor amelioration or elimination of the developed physical disease orcondition once it has been established or alleviation of thecharacteristic symptoms of such conditions.

As used herein, the term “medicament” also encompasses the terms “drug”,“therapeutic”, “potion” or other terms which are used in the field ofmedicine to indicate a preparation with therapeutic or prophylacticeffect.

The present inventor has not only found that the selective 5-HT2A and D4antagonists, inverse agonists or partial agonists have an effect inaugmenting the therapeutic effect or in providing a faster onset of thetherapeutic effect of selective serotonin re-uptake inhibitors, but alsothat this effect is seen in therapy with other pharmaceutical compounds.A few examples of other pharmaceutical compounds whose effects areaugmented or where the onset of the effect is fastened upon simultaneousor fore-going treatment with a 5-HT2A and D4 antagonist, inverse agonistor partial agonist, are nor-epinephrine re-uptake inhibitors,neuroleptic agents, NK1 antagonists or compounds used for treating oralleviating musculoskeletal diseases or disorders. It should be clear,given the general applicable character of the invention, that this listof other pharmaceutical compounds is very brief and that the inventionshould not be restricted to the ones exemplified herein.

According to the invention it thus has been found that the compoundshaving a selective 5-HT2A and D4 antagonist, inverse agonist or partialagonist activity as described above are useful for augmenting thetherapeutic effect of a second compound on a disease.

According to another embodiment of the invention it has also been foundthat the compounds having a selective 5-HT2A and D4 antagonist, inverseagonist or partial agonist activity as described above are useful forproviding a faster onset of the therapeutic effect of a second compoundon a disease.

In one embodiment, the compound having a selective 5-HT2A and D4antagonist, inverse agonist or partial agonist activity is used in acombination therapy with the second compound are to treat the samedisease or disorder, for instance a disease selected from the groupcomprising mood disorders, anxiety disorders, schizophrenia and otherpsychotic disorders, eating disorders, premenstrual syndrome, somatoformdisorders, factitious disorders, dissociative disorders, sexual andgender identity disorders, sleep disorders, adjustment disorders,cognitive disorders, impulse control disorders, pervasive development,attention-deficit and disruptive behaviour disorders, substance-relateddisorders, personality disorders, psychological factors affectingmedical conditions, malingering, antisocial behaviour, bereavement,occupational, identity, phase of life, academic problem, problemsrelated to abuse or neglect.

Preferably, said second compound is a nor-epinephrine re-uptakeinhibitor. Preferred nor-epinephrine re-uptake inhibitors to beadministered in combination with the selective 5-HT2A and D4 antagonist,inverse agonist or partial agonist of the invention are chosen from thegroup comprising tandamine, pirandamine, ciclazindol, fluparoxan,lortalamine, talsupram, talopram, prindamine, nomifensine, viloxazine,tomoxetine, duloxetine, venlafaxine, milnacipran and reboxetine,pharmaceutically acceptable salts, pro-drugs and mixtures thereof. Inother preferred embodiments, said second compound is a neurolepticagent. Preferred neuroleptic agents to be administered in combinationwith the selective 5-HT2A and D4 antagonist, inverse agonist or partialagonist of the invention are chosen from the group comprisingchlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine,trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone,ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole,blonanserin, iloperidone, perospirone, raclopride, zotepine, DU-127090,ORG-5222, SM-13496, amisulpride, CP-361428, Lu 35-138, balaperidone,S-18327, WAY-135452, eplivanserin, E-5842, SR-31742, NE-100, osanetant,SR-141716, SR-48692, BSF-201640, BSF-190555, LAX-101a, sarizotan, CX-691and SB-271046, pharmaceutically acceptable salts, pro-drugs or activemetabolites thereof, or mixtures thereof. In other preferredembodiments, said second compound is an NK1 antagonist. Preferred NK1antagonists to be administered in combination with the selective 5-HT2Aand D4 antagonist, inverse agonist or partial agonist of the inventionare chosen from the group comprising MK-0869, GW597599, GW679769,GW823296, Compound A, NKP608, CP-96,345(cis-3-(2-methoxybenzyl-amino-2-benzhydrylquinuclidine), CP-122721,CP-99994, GR-82334(D-Pro9-[Spiro-y-lactam]-Leu10,Trp11)-Physalaemin(1-11)), R673, TAK-637,RPR100893 (perhydroisoindolol), RP-67580, LY303870, SR-140333 andtrans-4-hydroxy-1-(1H-indol-3-ylcarbonyl)-L-prolyl-N-methyl-N-(phenylmethyl)-L-tyrosineamide(a derivative of FK888), pharmaceutically acceptable salts, pro-drugs oractive metabolites thereof, or mixtures thereof.

It should be noted that these compounds might be known under othernames. For instance ‘aprepitant’ is the generic name for MK-0869 whereasit is known as EMEND as its trademark name (Merck, Whitehouse Station,N.J.).

In alternative embodiments, the second compound is used to treat anotherdisease. In a preferred embodiment, said second compound is a COX-2inhibitor and is used for treating musculoskeletal diseases or for themanagement of acute pain or for primary treatment of dysmenorrhea, andthe first compound augments the therapeutic effect or provides for afaster onset of the therapeutic effect of said second compound on saidother disease.

Preferred COX-2 inhibitors to be administered in combination with theselective 5-HT2A and D4 antagonist, inverse agonist or partial agonistof the invention are chosen from the group comprising celecoxib,rofecoxib, meloxicam, piroxicam, deracoxib, parecoxib, valdecoxib,etoricoxib, a chromene derivative, a chroman derivative,N-(2-cyclohexyloxynitrophenyl)-methane sulfonamide, COX189, ABT963 orJTE-522, pharmaceutically acceptable salts, pro-drugs or activemetabolites thereof, or mixtures thereof.

From the above it should be clear that the selective 5-HT2A and D4antagonist, inverse agonist or partial agonist is also named ‘the firstcompound’ in the embodiments of the invention.

According to the invention, when the 5-HT2A and D4 antagonist, inverseagonist or partial agonist activity reside in separate compounds, theterm “composition” will be used. Compositions of the invention comprisea first compound having (i) a selective affinity for the D4 receptorwith a pKi value equal to or higher than 8 towards the D4 receptor andless than 8 towards other Dopamine receptors, and a second compoundhaving (ii) a selective affinity for the 5-HT2A receptor with a pKivalue equal to or higher than 8 towards the 5-HT2A receptor and lessthan 8 towards other 5HT receptors.

The expression “the 5-HT2A and D4 antagonist, inverse agonist or partialagonist” is used herein to indicate a single compound having bothactivities or to indicate the composition comprising the activity inseparate compounds.

It should be clear that when, in the present invention, a composition ofseparate compounds is used instead of a single compound, they may beused in combination with another, i.e. a third, compound to augment thetherapeutic effect of the other, i.e. the third, compound on the same oranother disease.

When the 5-HT2A and D4 antagonist, inverse agonist or partial agonistand the second compound or third compound, are administeredsimultaneously, the compounds or active ingredients may be present in asingle pharmaceutical composition or formulation. Alternatively thecompounds or active ingredients are administered in separatepharmaceutical compositions or formulations for simultaneous or separateuse.

When the 5-HT2A and D4 antagonist, inverse agonist or partial agonist ofthe invention is administered prior to the second or third compound, asdefined, the 5-HT2A and D4 antagonist, inverse agonist or partialagonist is administered at least during 1 day prior to said second orthird compound. Preferably the 5-HT2A and D4 antagonist, inverse agonistor partial agonist is administered for at least 1, 2 3, 4, 5, 6, 7, 8, 9or 10 days, prior to the administration of the second or third compound.Preferably the 5-HT2A and D4 antagonist, inverse agonist or partialagonist is administered for at least 2, 3, 4, 5 weeks prior to theadministration of the second or third compound, or for at least 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11 or 12 months prior to the administration of thesecond or third compound.

According to a preferred embodiment of the invention, the abovedescribed compounds having a 5-HT2A and D4 antagonist, inverse agonistor partial agonist activity are useful for augmenting the therapeuticeffect of CITALOPRAM or for providing a faster onset of the therapeuticeffect of CITALOPRAM.

CITALOPRAM or citalopram hydrobromide is a selective serotonin(5-hydroxytryptamine/5-HT) re-uptake inhibitor (SSRI) and is theconventional name given for the compound of the formula(RS)-1-[3-(dimethylamino)propyl]-1-(p-flurophenyl)-5-phthalancarbonitrile,hydro-bromide.

According to one embodiment, a daily doses of active ingredient of SSRI,preferably CITALOPRAM, ranges between 10 and 40 mg per day. Preferably,daily doses of active ingredient ranging between 20 and 30 mg per dayare administered. More preferably, a daily dose of 10, 15, 20, 25, 30,35 or 40 mg per day is administered.

Other preferred second or third compounds according to the invention arechosen from the group comprising selective serotonin re-uptakeinhibitors, for instance CITALOPRAM, fluoxetine, venlafaxine,fluvoxamine, paroxetine, sertraline, milnacipran and duloxetine; COX-2inhibitors, for instance celecoxib, rofecoxib, meloxicam, piroxicam,deracoxib, parecoxib, valdecoxib, etoricoxib, a chromene derivative, achroman derivative, N-(2-cyclohexyloxynitrophenyl) methane sulfonamide,COX189, ABT963 or JTE-522; nor-epinephrine re-uptake inhibitors, forinstance tandamine, pirandamine, ciclazindol, fluparoxan, lortalamine,talsupram, talopram, prindamine, nomifensine, viloxazine, tomoxetine,duloxetine, venlafaxine, milnacipran and reboxetine; and neurolepticagents, for instance chlorpromazine, haloperidol, perphenazine,thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine,olanzapine, risperidone, ziprasidone, quetiapine, sertindole,aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone,raclopride, zotepine, DU-127090, ORG-5222, SM-13496, amisulpride,CP-361428, Lu 35-138, balaperidone, S-18327, WAY-135452, eplivanserin,E-5842, SR-31742, NE-100, osanetant, SR-141716, SR-48692, BSF-201640,BSF-190555, LAX-101a, sarizotan, CX-691 and SB-271046; and NK1antagonists, for instance MK-0869, GW597599, GW679769, GW823296,Compound A, NKP608, CP-96,345(cis-3-(2-methoxybenzyl-amino-2-benzhydrylquinuclidine), CP-122721,CP-99994, GR-82334(D-Pro9-[Spiro-y-lactam]-Leu10,Trp11)-Physalaemin(1-11)), R673, TAK-637,RPR100893 (perhydroisoindolol), RP-67580, LY303870, SR-140333 andtrans-4-hydroxy-1-(1H-indol-3-ylcarbonyl)-L-prolyl-N-methyl-N-(phenylmethyl)-L-tyrosineamide(a derivative of FK888). All these compounds are known in the art andare to be used in doses according to the supplier's or physician'sprescription. Preferably, MK-0869 is used in doses ranging from 10 to160 mg, more preferably a dose of 80 mg is administered.

Also encompassed by the invention are pro-drugs to these second or thirdcompounds or active metabolites of these compounds. For instance, forrisperidone it is known that, among other products, biotransformation inthe liver produces 9-hydroxyrisperidone, which is of the samepharmacological activity and intensity as parent risperidone. Therefore,also 9-hydroxyrisperidone, naturally produced or chemically synthesizedmay be used in the methods of the invention.

The term “active metabolite” as used herein relates to a therapeuticallyactive compound produced by the metabolism of a parent drug. Drugsadministered to treat diseases are usually transformed (metabolized)within the body into a variety of related chemical forms (metabolites),some of which may have therapeutic activity (an active metabolite).

According to a yet more specific embodiment, the invention relates to amethod for treating a disease or disorder with an underlyingdysregulation of the emotional functionality comprising the use ofPIPAMPERONE, further characterised in that PIPAMPERONE is administeredsimultaneously with, separate from or sequential to an NK1 antagonist toaugment the therapeutic effect of said NK1 antagonist, or to provide afaster onset of the therapeutic effect of said NK1 antagonist;preferably said NK1 antagonist is chosen from the group comprisingMK-0869, GW597599, GW679769, GW823296, Compound A, NKP608, CP-96,345(cis-3-(2-methoxybenzyl-amino-2-benzhydrylquinuclidine), CP-122721,CP-99994, GR-82334(D-Pro9-[Spiro-y-lactam]-Leu10,Trp11)-Physalaemin(1-11)), R673, TAK-637,RPR100893 (perhydroisoindolol), RP-67580, LY303870, SR-140333 andtrans-4-hydroxy-1-(1H-indol-3-ylcarbonyl)-L-prolyl-N-methyl-N-(phenylmethyl)-L-tyrosineamide(a derivative of FK888), or a pro-drug or an active metabolite thereof,or a pharmaceutically acceptable salt thereof; more preferably said NK1antagonist is MK-0869 and is administered in a dose ranging between 10and 160 mg of the active ingredient; even more preferably said NK1antagonist is administered in a dose of 80 mg of the active ingredient.In an even most preferred embodiment PIPAMPERONE, which is administeredsimultaneously with, separate from or prior to MK-0869, is administeredin a dose ranging between 5 to 15 mg of the active ingredient.

The present invention also encompasses the use of these second or thirdcompounds, administered in the form of a pharmaceutically acceptablesalt in admixture with a suitable pharmaceutically acceptable excipient.

To prepare the pharmaceutical compositions, comprising the compounds orthe combination of the first and second compound described herein, aneffective amount of the active ingredients, in acid or base additionsalt form or base form, is combined in admixture with a pharmaceuticallyacceptable carrier, which can take a wide variety of forms depending onthe form of preparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, foradministration orally, nasal, rectally, percutaneously or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included.

According to a further embodiment, the invention also relates to amethod for preparing a compound having a selective D4 and 5-HT2Aantagonist, reverse agonist or partial agonist. The invention alsorelates to the compounds prepared by the claimed method, with theproviso that said compound is not an already known compound, such asPIPAMPERONE.

It should be clear that the compounds and compositions described hereinare useful for treating any patient in need thereof. As used herein theterm “patient” is not restricted to humans but also to other mammals,for instance domestic animals which may also suffer from any form of amental disease or disorder described herein.

The invention, now being generally described, will be more readilyunderstood by reference to the following tables and examples, which areincluded merely for purposes of illustration of certain aspects andembodiments of the present invention and are not intended to limit theinvention.

EXAMPLES Example 1 Measuring pKi Values of Test Compounds

In Table 1, the pKi values of test compounds are given for each of thedopamine receptors, 5HT receptors, adrenergic receptors and thehistaminel receptor. The affinity of test compounds for the respectivereceptors has been performed according to conventional procedures knownin the art.

An indication “0” means that no affinity has been measured between thetest compound and the receptor.

The columns displaying the pKi values for the D4 and the 5-HT2A receptorare filled with dark grey. pKi values between 8 and 9 and higher than 9are represented by light grey boxes.

Example 2 Foregoing Pipamperon-Citalopram Treatment in Mayor DepressiveDisorder: a Placebo and Active Controlled Period Finding Clinical Trial

Table 2 represents the set-up of a clinical trial comprising fortreatment groups:

Group Plc—Active/Day 0 represents the group receiving 10 mg citalopram,twice a day, starting the first day (Day 0) of active treatment in theclinical trial. This administration regime is also indicated as the monotherapy.

Group Pip—Active/Day 0 represents the group receiving a combination of 4mg pipamperon and 10 mg citalopram, twice a day, starting the first day(Day 0) of active treatment in the clinical trial. This administrationregime is also indicated as the non-foregoing combo therapy.

Group Pip—Active/Day 4 represents the group receiving 4 mg pipamperon,twice a day, starting the first day (Day 0) of active treatment in theclinical trial, followed by a combination of 4 mg pipamperon and 10 mgcitalopram, twice a day, starting the fifth (Day 4) day of activetreatment in the clinical trial. This administration regime is alsoindicated as the foregoing therapy with combination therapy startingafter 4 days of active treatment.

Group Pip—Active/Day 7 represents the group receiving 4 mg pipamperon,twice a day, starting the first day (Day 0) of active treatment in theclinical trial, followed by a combination of 4 mg pipamperon and 10 mgcitalopram, twice a day, starting the eight (Day 7) day of activetreatment in the clinical trial. This administration regime is alsoindicated as the foregoing therapy with combination therapy startingafter 7 days of active treatment.

All subjects also undergo a placebo (PLC) run-in therapy, administeredduring a period of about 7 days before the active treatment starts.

During daily (D), weekly (W) or monthly (M) visits, several parametersare measured.

Under NECT is to be understood: Neuronal E-clinical Trial=VesaliusExpert development for this trial which includes the bottom-upmeasurement of:

-   -   In- and exclusion-criteria    -   Functional status evaluation    -   Medical history    -   (Pre-)treatment signs & symptoms    -   DSM-IV rules for diagnosis & efficacy    -   HDRS-28 (Hamilton Depression Rating Scale—28 items)    -   Medical resource utilisation    -   Pre-trial & Concomittant medication    -   Drug administration    -   (Serious) Adverse events    -   Admission to the acute and extension phase of treatment

Right flow of the trial TABLE 1

TABLE 2 ACUTE PHASE** FOLLOW- V2 UP VISITS V1 Base- EXTENSION PHASE***PHASE Day/Week/ Screen line V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15V16 V17 V18 V19 Month minus D7 D0 D4 D7 W2 W3 W4 W6 W8 W10 W12 W16 W20W24 M8 M10 M12 W1 W2 TREAT- MENT- GROUP Group Pip- A B B C A A Active/D7Group Pip- A B C A A Active/D4 Group Pip- A C A A Active/D0 Group Pic- AD A A Active/D0 Informed x Consent NECT* x x x x x x x x x x x x x x x xx x x Vital Signs/ x x x x Weight LAB x x x x ECG x x x x Phys x ExamAlc/Drugs x x x x Screen CGI- x x x x x x x x x x x x x x x x x x xS**** Q-LES- Q*****Treatment regimen:A: PLC + PLCB: 2 × (PLC + PIP(4 mg))/dC: 2 × (CIT(10 mg) + PIP(4 mg))/dD: 2 × (CIT(10 mg) + PLC)/d*Neuronal E-Clinical Trial = Vesalius Expert Development for this Trialwhich includes the bottom-up measurement of:**Entering Acute Phase: only NON-placebo responders as defined by theDSM-IV criteria of efficacy***Entering Extension Phase: only remittors as defined by the DSM-IVcriteria of efficacy****CGI-S: Clinical Global Impressions-Improvement Scale*****Q-LES-Q: Quality of Life, Enjoyment and Satisfaction Questionnaire

1. A method for treating a disease or disorder with an underlyingdysregulation of emotional functionality comprising administering to apatient a compound having (i) a selective affinity for the Dopamine-4(D4) receptor with a pKi value equal to or higher than 8 towards the D4receptor and less than 8 towards other Dopamine receptors, and (ii) aselective affinity for the 5-HT2A receptor with a pKi value equal to orhigher than 8 towards the 5-HT2A receptor and less than 8 towards other5HT receptors, wherein said compound is administered to said patient ina dose ranging between 5 and 15 mg of the active ingredient.
 2. Themethod of claim 1 wherein said compound is PIPAMPERONE.
 3. The method ofclaim 2, wherein said disease or disorder is selected from the groupconsisting of anxiety disorders, eating disorders, premenstrualsyndrome, somatoform disorders, factitious disorders, dissociativedisorders, sexual and gender identity disorders, sleep disorders,adjustment disorders, cognitive disorders, impulse control disorders,pervasive development, attention-deficit and disruptive behaviourdisorders, substance-related disorders, personality disorders,psychological factors affecting medical conditions, malingering,antisocial behaviour, bereavement, occupational, identity, phase oflife, academic problem, and problems related to abuse or neglect.
 4. Themethod of claim 1 further comprising administering to the patient asecond compound simultaneously with, separate from or sequential to afirst compound as defined in claim 1 to augment the therapeutic effectof said second compound or to provide a faster onset of the therapeuticeffect of said second compound.
 5. (canceled)
 6. The method of claim 4,wherein said second compound has a therapeutic effect on a disease ordisorder selected from the group consisting of mood disorders, anxietydisorders, schizophrenia and other psychotic disorders, eatingdisorders, premenstrual syndrome, somatoform disorders, factitiousdisorders, dissociative disorders, sexual and gender identity disorders,sleep disorders, adjustment disorders, cognitive disorders, impulsecontrol disorders, pervasive development, attention-deficit anddisruptive behaviour disorders, substance-related disorders, personalitydisorders, psychological factors affecting medical conditions,malingering, antisocial behaviour, bereavement, occupational, identity,phase of life, academic problem, and problems related to abuse orneglect.
 7. The method of claim 4, wherein the first compound isadministered daily at least one day before administering said secondcompound.
 8. The method of claim 4, wherein said second compound is aselective serotonin re-uptake inhibitor.
 9. The method of claim 8,wherein said selective serotonin re-uptake inhibitor is chosen from thegroup consisting of CITALOPRAM, fluoxetine, venlafaxine, fluvoxamine,paroxetine, sertraline, milnacipran and duloxetine or a pro-drug or anactive metabolite thereof, or a pharmaceutically acceptable saltthereof.
 10. The method of claim 9 wherein said serotonin re-uptakeinhibitor is CITALOPRAM and is administered in a dose ranging between 10and 40 mg of the active ingredient.
 11. A method for treating a diseaseor disorder with an underlying dysregulation of emotional functionalitycomprising administering to a patient a first compound having (i) aselective affinity for the D4 receptor with a pKi value equal to orhigher than 8 towards the D4 receptor and less than 8 towards otherDopamine receptors, and a second compound having (ii) a selectiveaffinity for the 5-HT2A receptor with a pKi value equal to or higherthan 8 towards the 5-HT2A receptor and less than 8 towards other 5HTreceptors.
 12. The method of claim 11, wherein said disease or disorderis selected from the group consisting of mood disorders, anxietydisorders, schizophrenia and other psychotic disorders, eatingdisorders, premenstrual syndrome, somatoform disorders, factitiousdisorders, dissociative disorders, sexual and gender identity disorders,sleep disorders, adjustment disorders, cognitive disorders, impulsecontrol disorders, pervasive development, attention-deficit anddisruptive behaviour disorders, substance-related disorders, personalitydisorders, psychological factors affecting medical conditions,malingering, antisocial behaviour, bereavement, occupational, identity,phase of life, academic problem, and problems related to abuse orneglect.
 13. The method of claim 11, wherein said first compound ischosen from the group consisting of PIPAMPERONE, FANANSERIN, L-745,870,PNU-101387G and U-1013871, and wherein said second compound is chosenfrom the group consisting of PIPAMPERONE, FANANSERIN, ORG 5222,ZOTEPINE, OLANZEPINE, CLOZAPINE, S16924, S18327, AMPEROZIDE, SERTINDOLE,MDL 100.907, TIOSPIRONE, FLUSPIRILENE, OCAPERIDONE, RISPERIDONE andZIPRASIDONE, or a pro-drug or an active metabolite thereof, or apharmaceutically acceptable salt thereof.
 14. The method of claim 11,wherein said compounds are administered to said a patient in a doseranging between 0.5 μg and 300 mg for each of the active ingredients.15. The method of claim 11, wherein the first compound and the secondcompound are administered simultaneously with, separate from orsequential to a third compound to augment the therapeutic effect of saidthird compound or to provide a faster onset of the therapeutic effect ofsaid third compound.
 16. (canceled)
 17. The method of claim 15, whereinsaid third compound is a selective serotonin re-uptake inhibitor. 18.The method of claim 17, wherein said selective serotonin re-uptakeinhibitor is chosen from the group consisting of CITALOPRAM, fluoxetine,venlafaxine, fluvoxamine, paroxetine, sertraline, milnacipran andduloxetine, or a pro-drug or an active metabolite thereof, or apharmaceutically acceptable salt thereof.
 19. The method of claim 18wherein said serotonin re-uptake inhibitor is CITALOPRAM and isadministered in a dose ranging between 10 and 40 mg of the activeingredient.
 20. A method for treating a disease or disorder with anunderlying dysregulation of emotional functionality comprisingadministering to a patient a compound as defined in claim 1 where thecompound is administered simultaneously with, separate from orsequential to administering to said patient a nor-epinephrine re-uptakeinhibitor to augment the therapeutic effect of said nor-epinephrinere-uptake inhibitor or to provide a faster onset of the therapeuticeffect of said nor-epinephrine re-uptake inhibitor.
 21. A method fortreating a disease or disorder with an underlying dysregulation of theemotional functionality comprising administering to a patient a firstcompound and a second compound as defined in claim 11 where saidcompounds are administered simultaneously with, separate from orsequential to administering a nor-epinephrine re-uptake inhibitor tosaid patient to augment the therapeutic effect of said nor-epinephrinere-uptake inhibitor or to provide a faster onset of the therapeuticeffect of said nor-epinephrine re-uptake inhibitor.
 22. The methodaccording to claim 20, wherein said nor-epinephrine re-uptake inhibitoris chosen from the group consisting of tandamine, pirandamine,ciclazindol, fluparoxan, lortalamine, talsupram, talopram, prindamine,nomifensine, viloxazine, tomoxetine, duloxetine, venlafaxine,milnacipran and reboxetine, or a pro-drug or an active metabolitethereof, or a pharmaceutically acceptable salt thereof.
 23. A method fortreating a disease or disorder with an underlying dysregulation of theemotional functionality comprising administering to a patient a compoundas defined in claim 1 where the compound is administered simultaneouslywith, separate from or sequential to administering to said patient aneuroleptic agent to augment the therapeutic effect of said neurolepticagent or to provide a faster onset of the therapeutic effect of saidneuroleptic agent.
 24. A method for treating a disease or disorder withan underlying dysregulation of the emotional functionality comprisingadministering to a patient a first compound and a second compound asdefined in claim 11 where said compounds are administered simultaneouslywith, separate from or sequential to administering a neuroleptic agentto said patient to augment the therapeutic effect of said neurolepticagent or to provide a faster onset of the therapeutic effect of saidneuroleptic agent.
 25. The method according to claim 23, wherein saidneuroleptic agent is chosen from the group consisting of chlorpromazine,haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine,fluphenazine, clozapine, olanzapine, risperidone, ziprasidone,quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin,iloperidone, perospirone, raclopride, zotepine, DU-127090, ORG-5222,SM-13496, amisulpride, CP-361428, Lu 35-138, balaperidone, S-18327,WAY-135452, eplivanserin, E-5842, SR-31742, NE-100, osanetant,SR-141716, SR-48692, BSF-201640, BSF-190555, LAX-101a, sarizotan, CX-691and SB-271046, or a pro-drug or active metabolite thereof, or apharmaceutically acceptable salt thereof.
 26. A method for treating adisease or disorder with an underlying dysregulation of the emotionalfunctionality comprising administering to a patient a compound asdefined in claim 1 where the compound is administered simultaneouslywith, separate from or sequential to administering to said patient anNK1 antagonist to augment the therapeutic effect of said NK1 antagonistor to provide a faster onset of the therapeutic effect of said NK1antagonist.
 27. A method for treating a disease or disorder with anunderlying dysregulation of emotional functionality comprisingadministering to a patient a first compound and a second compound asdefined in claim 11 where said compounds are administered simultaneouslywith, separate from or sequential to administering an NK1 antagonist tosaid patient to augment the therapeutic effect of said NK1 antagonist orto provide a faster onset of the therapeutic effect of said NK1antagonist.
 28. The method according to claim 26, wherein said NK1antagonist is chosen from the group consisting of MK-0869, GW597599,GW679769, GW823296, Compound A, NKP608, CP-96,345(cis-3-(2-methoxybenzyl-amino-2-benzhydrylquinuclidine), CP-122721,CP-99994, GR-82334(D-Pro9-[Spiro-y-lactam]-Leu10,Trp11)-Physalaemin(1-11)), R673, TAK-637,RPR100893 (perhydroisoindolol), RP-67580, LY303870, SR-140333 andtrans-4-hydroxy-1-(1H-indol-3-ylcarbonyl)-L-prolyl-N-methyl-N-(phenylmethyl)-L-tyrosineamide(a derivative of FK888), or a pro-drug or an active metabolite thereof,or a pharmaceutically acceptable salt thereof.
 29. The method accordingto claim 28 wherein said NK1 antagonist is MK-0869 and is administeredin a dose ranging between 10 and 160 mg of the active ingredient. 30.The method according to claim 29 wherein MK-0869 is administered in adose of 80 mg of the active ingredient.
 31. The method according toclaim 26, wherein the compound having (i) a selective affinity for theDopamine-4 (D4) receptor with a pKi value equal to or higher than 8towards the D4 receptor and less than 8 towards other Dopaminereceptors, and (ii) a selective affinity for the 5-HT2A receptor with apKi value equal to or higher than 8 towards the 5-HT2A receptor and lessthan 8 towards other 5HT receptors serotonin re-uptake inhibitor isPIPAMPERONE.
 32. The method according to claim 31, wherein PIPAMPERONEis administered to the patient in a dose ranging between 5 and 15 mg ofthe active ingredient and wherein MK-0869 is administered to the patientin a dose ranging between 10 and 160 mg of the active ingredient.
 33. Amethod for treating a muscoskeletal disease or disorder comprisingadministering to a patient a compound as defined in claim 1 where thecompound is administered simultaneously with, separate from orsequential to administering to said patient a COX-2 inhibitor to augmentthe therapeutic effect of said COX-2 inhibitor or to provide a fasteronset of the therapeutic effect of said COX-2 inhibitor.
 34. A methodfor treating a muscoskeletal disease or disorder comprisingadministering to a patient a first compound and a second compound asdefined in claim 11, where said compounds are administeredsimultaneously with, separate from or sequential to administering aCOX-2 inhibitor to said patient to augment the therapeutic effect ofsaid COX-2 inhibitor or to provide a faster onset of the therapeuticeffect of said COX-2 inhibitor.
 35. The method of claim 33, wherein saiddisease or disorder is selected from the group consisting of rheumatoidarthritis, osteoarthritis and ankylosing spondylitis.
 36. The method ofclaim 33, wherein said COX-2 inhibitor is chosen from the groupconsisting of celecoxib, rofecoxib, meloxicam, piroxicam, deracoxib,parecoxib, valdecoxib, etoricoxib, a chromene derivative, a chromanderivative, N-(2-cyclohexyloxynitrophenyl)methane sulfonamide, COX189,ABT963 and JTE-522, or a pro-drug or active metabolite thereof, or apharmaceutically acceptable salt thereof.
 37. A method for preparing acompound having a selective D4 and 5-HT2A antagonist, reverse agonist orpartial agonist activity comprising the following steps: (a) measuringthe selective affinity of a test compound to the D4 receptor andselecting a compound that has a pKi value equal to or greater than 8towards the D4 receptor in respect to all the other D receptors, andmeasuring the selective efficacy of the selected compound to the D4receptor and selecting a compounds which is a selective antagonist,inverse agonist or partial agonist of the D4 receptor; (b) measuring theselective affinity of a test compound to the 5-HT2A receptor andselecting a compound that has a pKi value equal to or greater than 8towards the 5-HT2A receptor in respect to all the other 5HT receptors,and measuring the selective efficacy of the selected compound to the5-HT2A receptor and selecting a compounds which is a selectiveantagonist, inverse agonist or partial agonist of the 5-HT2A receptor;(c) identifying a compound which is selected in (a) and (b), (d)preparing the compound identified in (c).
 38. Compound prepared by themethod of claim
 37. 39. The method according to claim 21, wherein saidnor-epinephrine re-uptake inhibitor is chosen from the group consistingof tandamine, pirandamine, ciclazindol, fluparoxan, lortalamine,talsupram, talopram, prindamine, nomifensine, viloxazine, tomoxetine,duloxetine, venlafaxine, milnacipran and reboxetine, or a pro-drug or anactive metabolite thereof, or a pharmaceutically acceptable saltthereof.
 40. The method of claim 20, wherein said disease or disorder isselected from the group consisting of mood disorders, anxiety disorders,schizophrenia and other psychotic disorders, eating disorders,premenstrual syndrome, somatoform disorders, factitious disorders,dissociative disorders, sexual and gender identity disorders, sleepdisorders, adjustment disorders, cognitive disorders, impulse controldisorders, pervasive development, attention-deficit and disruptivebehaviour disorders, substance-related disorders, personality disorders,psychological factors affecting medical conditions, malingering,antisocial behaviour, bereavement, occupational, identity, phase oflife, academic problem, and problems related to abuse or neglect. 41.The method of claim 21, wherein said disease or disorder is selectedfrom the group consisting of mood disorders, anxiety disorders,schizophrenia and other psychotic disorders, eating disorders,premenstrual syndrome, somatoform disorders, factitious disorders,dissociative disorders, sexual and gender identity disorders, sleepdisorders, adjustment disorders, cognitive disorders, impulse controldisorders, pervasive development, attention-deficit and disruptivebehaviour disorders, substance-related disorders, personality disorders,psychological factors affecting medical conditions, malingering,antisocial behaviour, bereavement, occupational, identity, phase oflife, academic problem, and problems related to abuse or neglect. 42.The method according to claim 24, wherein said neuroleptic agent ischosen from the group consisting of chlorpromazine, haloperidol,perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine,clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole,aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone,raclopride, zotepine, DU-127090, ORG-5222, SM-13496, amisulpride,CP-361428, Lu 35-138, balaperidone, S-18327, WAY-135452, eplivanserin,E-5842, SR-31742, NE-100, osanetant, SR-141716, SR-48692, BSF-201640,BSF-190555, LAX-101a, sarizotan, CX-691 and SB-271046, or a pro-drug oractive metabolite thereof, or a pharmaceutically acceptable saltthereof.
 43. The method of claim 23, wherein said disease or disorder isselected from the group consisting of mood disorders, anxiety disorders,schizophrenia and other psychotic disorders, eating disorders,premenstrual syndrome, somatoform disorders, factitious disorders,dissociative disorders, sexual and gender identity disorders, sleepdisorders, adjustment disorders, cognitive disorders, impulse controldisorders, pervasive development, attention-deficit and disruptivebehaviour disorders, substance-related disorders, personality disorders,psychological factors affecting medical conditions, malingering,antisocial behaviour, bereavement, occupational, identity, phase oflife, academic problem, and problems related to abuse or neglect. 44.The method of claim 24, wherein said disease or disorder is selectedfrom the group consisting of mood disorders, anxiety disorders,schizophrenia and other psychotic disorders, eating disorders,premenstrual syndrome, somatoform disorders, factitious disorders,dissociative disorders, sexual and gender identity disorders, sleepdisorders, adjustment disorders, cognitive disorders, impulse controldisorders, pervasive development, attention-deficit and disruptivebehaviour disorders, substance-related disorders, personality disorders,psychological factors affecting medical conditions, malingering,antisocial behaviour, bereavement, occupational, identity, phase oflife, academic problem, and problems related to abuse or neglect. 45.The method according to claim 27, wherein said NK1 antagonist is chosenfrom the group consisting of MK-0869, GW597599, GW679769, GW823296,Compound A, NKP608, CP-96,345(cis-3-(2-methoxybenzyl-amino-2-benzhydrylquinuclidine), CP-122721,CP-99994, GR-82334(D-Pro9-[Spiro-y-lactam]-Leu10,Trp11)-Physalaemin(1-11)), R673, TAK-637,RPR100893 (perhydroisoindolol), RP-67580, LY303870, SR-140333 andtrans-4-hydroxy-1-(1H-indol-3-ylcarbonyl)-L-prolyl-N-methyl-N-(phenylmethyl)-L-tyrosineamide(a derivative of FK888), or a pro-drug or an active metabolite thereof,or a pharmaceutically acceptable salt thereof.
 46. The method accordingto claim 45, wherein said NK1 antagonist is MK-0869 and is administeredin a dose ranging between 10 and 160 mg of the active ingredient. 47.The method according to claim 46, wherein MK-0869 is administered in adose of 80 mg of the active ingredient.
 48. The method of claim 26,wherein said disease or disorder is selected from the group consistingof mood disorders, anxiety disorders, schizophrenia and other psychoticdisorders, eating disorders, premenstrual syndrome, somatoformdisorders, factitious disorders, dissociative disorders, sexual andgender identity disorders, sleep disorders, adjustment disorders,cognitive disorders, impulse control disorders, pervasive development,attention-deficit and disruptive behaviour disorders, substance-relateddisorders, personality disorders, psychological factors affectingmedical conditions, malingering, antisocial behaviour, bereavement,occupational, identity, phase of life, academic problem, and problemsrelated to abuse or neglect.
 49. The method of claim 27, wherein saiddisease or disorder is selected from the group consisting of mooddisorders, anxiety disorders, schizophrenia and other psychoticdisorders, eating disorders, premenstrual syndrome, somatoformdisorders, factitious disorders, dissociative disorders, sexual andgender identity disorders, sleep disorders, adjustment disorders,cognitive disorders, impulse control disorders, pervasive development,attention-deficit and disruptive behaviour disorders, substance-relateddisorders, personality disorders, psychological factors affectingmedical conditions, malingering, antisocial behaviour, bereavement,occupational, identity, phase of life, academic problem, and problemsrelated to abuse or neglect.
 50. The method of claim 34, wherein saiddisease or disorder is selected from the group consisting of rheumatoidarthritis, osteoarthritis and ankylosing spondylitis.
 51. The method ofclaim 34, wherein said COX-2 inhibitor is chosen from the groupconsisting of celecoxib, rofecoxib, meloxicam, piroxicam, deracoxib,parecoxib, valdecoxib, etoricoxib, a chromene derivative, a chromanderivative, N-(2-cyclohexyloxynitrophenyl)methane sulfonamide, COX189,ABT963 and JTE-522, or a pro-drug or active metabolite thereof, or apharmaceutically acceptable salt thereof.
 52. A pharmaceuticalcomposition comprising: (a) a compound having (i) a selective affinityfor the Dopamine-4 (D4) receptor with a pKi value equal to or higherthan 8 towards the D4 receptor and less than 8 towards other Dopaminereceptors, and (ii) a selective affinity for the 5-HT2A receptor with apKi value equal to or higher than 8 towards the 5-HT2A receptor and lessthan 8 towards other 5HT receptors, and (b) a selective serotoninre-uptake inhibitor, as a combined preparation for simultaneous,separate or sequential use for treating a disease or disorder with anunderlying dysregulation of emotional functionality as defined in claim6.
 53. The pharmaceutical composition according to claim 52 comprising:(a) pipamperone in a dose ranging between 5 and 15 mg of the activeingredient, and (b) citalopram in a dose ranging between 10 and 40 mg ofthe active ingredient.
 54. A pharmaceutical composition comprising: (a)a compound having a selective affinity for the Dopamine-4 (D4) receptorwith a pKi value equal to or higher than 8 towards the D4 receptor andless than 8 towards other Dopamine receptors, (b) a compound having aselective affinity for the 5-HT2A receptor with a pKi value equal to orhigher than 8 towards the 5-HT2A receptor and less than 8 towards other5HT receptors, and (c) a selective serotonin re-uptake inhibitor, as acombined preparation for simultaneous, separate or sequential use fortreating a disease or disorder with an underlying dysregulation ofemotional functionality as defined in claim
 12. 55. A pharmaceuticalcomposition comprising: (a) a compound having (i) a selective affinityfor the Dopamine-4 (D4) receptor with a pKi value equal to or higherthan 8 towards the D4 receptor and less than 8 towards other Dopaminereceptors, and (ii) a selective affinity for the 5-HT2A receptor with apKi value equal to or higher than 8 towards the 5-HT2A receptor and lessthan 8 towards other 5HT receptors and (b) a nor-epinephrine re-uptakeinhibitor, as a combined preparation for simultaneous, separate orsequential use for treating a disease or disorder with an underlyingdysregulation of emotional functionality as defined in claim
 12. 56. Apharmaceutical composition comprising: (a) a compound having a selectiveaffinity for the Dopamine-4 (D4) receptor with a pKi value equal to orhigher than 8 towards the D4 receptor and less than 8 towards otherDopamine receptors, (b) a compound having a selective affinity for the5-HT2A receptor with a pKi value equal to or higher than 8 towards the5-HT2A receptor and less than 8 towards other 5HT receptors, and (c) anor-epinephrine re-uptake inhibitor, as a combined preparation forsimultaneous, separate or sequential use for treating a disease ordisorder with an underlying dysregulation of the emotional functionalityas defined in claim
 12. 57. A pharmaceutical composition comprising: (a)a compound having (i) a selective affinity for the Dopamine-4 (D4)receptor with a pKi value equal to or higher than 8 towards the D4receptor and less than 8 towards other Dopamine receptors, and (ii) aselective affinity for the 5-HT2A receptor with a pKi value equal to orhigher than 8 towards the 5-HT2A receptor and less than 8 towards other5HT receptors, and (b) a neuroleptic agent, as a combined preparationfor simultaneous, separate or sequential use for treating a disease ordisorder with an underlying dysregulation of emotional functionality asdefined in claim
 12. 58. A pharmaceutical composition comprising: (a) acompound having a selective affinity for the Dopamine-4 (D4) receptorwith a pKi value equal to or higher than 8 towards the D4 receptor andless than 8 towards other Dopamine receptors, (b) a compound having aselective affinity for the 5-HT2A receptor with a pKi value equal to orhigher than 8 towards the 5-HT2A receptor and less than 8 towards other5HT receptors, and (c) a neuroleptic agent, as a combined preparationfor simultaneous, separate or sequential use for treating a disease ordisorder with an underlying dysregulation of emotional functionality asdefined in claim
 12. 59. A pharmaceutical composition comprising: (a) acompound having (i) a selective affinity for the Dopamine-4 (D4)receptor with a pKi value equal to or higher than 8 towards the D4receptor and less than 8 towards other Dopamine receptors, and (ii) aselective affinity for the 5-HT2A receptor with a pKi value equal to orhigher than 8 towards the 5-HT2A receptor and less than 8 towards other5HT receptors, and (b) an NK1 antagonist, as a combined preparation forsimultaneous, separate or sequential use for treating a disease ordisorder with an underlying dysregulation of emotional functionality asdefined in claim
 12. 60. A pharmaceutical composition comprising: (a) acompound having a selective affinity for the Dopamine-4 (D4) receptorwith a pKi value equal to or higher than 8 towards the D4 receptor andless than 8 towards other Dopamine receptors, (b) a compound having aselective affinity for the 5-HT2A receptor with a pKi value equal to orhigher than 8 towards the 5-HT2A receptor and less than 8 towards other5HT receptors, and (c) an NK1 antagonist, as a combined preparation forsimultaneous, separate or sequential use for treating a disease ordisorder with an underlying dysregulation of emotional functionality asdefined in claim
 12. 61. The pharmaceutical composition according toclaim 59 comprising: (a) pipamperone in a dose ranging between 5 and 15mg of the active ingredient, and (b) MK-0869 in a dose ranging between10 and 160 mg of the active ingredient.
 62. A pharmaceutical compositioncomprising: (a) a compound having (i) a selective affinity for theDopamine-4 (D4) receptor with a pKi value equal to or higher than 8towards the D4 receptor and less than 8 towards other Dopaminereceptors, and (ii) a selective affinity for the 5-HT2A receptor with apKi value equal to or higher than 8 towards the 5-HT2A receptor and lessthan 8 towards other 5HT receptors, and (b) a COX-2 inhibitor, as acombined preparation for simultaneous, separate or sequential use fortreating a muscoskeletal disease or disorder.
 63. A pharmaceuticalcomposition comprising: (a) a compound having a selective affinity forthe Dopamine-4 (D4) receptor with a pKi value equal to or higher than 8towards the D4 receptor and less than 8 towards other Dopaminereceptors, (b) a compound having a selective affinity for the 5-HT2Areceptor with a pKi value equal to or higher than 8 towards the 5-HT2Areceptor and less than 8 towards other 5HT receptors, and (c) a COX-2inhibitor, as a combined preparation for simultaneous, separate orsequential use for treating a muscoskeletal disease or disorder.